Apparatus, systems, and methods for continuous manufacturing of nanomaterials and high purity chemicals

ABSTRACT

A method for continuously processing at least two liquid feed streams is provided. A system for continuously processing at least two liquid feed streams is also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to U.S. Provisional Pat. Appln.Ser. No. 62/688,755 filed on Jun. 22, 2018 and U.S. Provisional Pat.Appln. Ser. No. 62/788,298 filed on Jan. 4, 2019, the contents of eachapplication incorporated herein by reference in their entireties.

FIELD OF THE DISCLOSURE

The present disclosure is directed to apparatus, systems, and methodsthat facilitate highly effective molecular contact within a definedreaction chamber, thereby enhancing and/or promoting a host of mixingand/or reaction phenomena. More particularly, the disclosed apparatus,systems, and methods are designed to enhance mixing of continuousstreams of liquids that are fed into a microreactor so as to producenanomaterials, enhance the rates of chemical reactions, or improve thepurity of the products of the chemical reactions.

BACKGROUND

The role of hydrodynamics should not be underestimated in any facet ofthe engineering sciences. The flow patterns within process units andtheir associated transfer lines have a significant impact upon mass,energy and momentum transport rates and reaction proficiency. Thus,system designs generally benefit from the identification of energydissipation mechanisms and, thus, quantification of the intensity ofmixing and contact efficacy. These factors are generally important inmaterials handling and manufacturing processes.

For example, the intensity of turbulence generally influences the sizeof particles that are dispersed throughout a fluid, the quality of anemulsion, and the residence time distribution profiles that determineprogress and selectivity of chemical reactions. This is particularlyapparent in the emerging nanotechnologies, where precipitation andcrystallization processes have a significant impact on product quality.Furthermore, mixing characteristics influence and/or determine theperformance of reaction vessels, at both laboratory and productionscales, and properly designed/implemented mixing systems can permitand/or facilitate the use of continuous systems, in lieu of batchsystems, to enhance productivity.

In terms of mixing technologies, cavitation has been used in industryfor homogenization operations, i.e., to disperse suspended particles incolloidal liquids. Numerous engineering principles are involved withcavitation behavior (see, e.g., Christopher Earls Brennen, “Cavitationand Bubble Dynamics”, Oxford University Press (1995)). Althoughcavitation-based mixing is often employed with solids, it may not be thebest choice for generation of nanoemulsions and vesicle loading, as indrug chaperones. Cavitation can result in issues associated withmaterials of construction and/or scale-up issues for mixing devicefabrication. In particular, by forcing a liquid through an annularopening that has a narrow entrance orifice with a much larger exitorifice, a dramatic decrease in pressure results in fluid accelerationinto a larger volume and generation of cavitation bubbles. The surfaceupon which these bubbles collide (causing their implosion) is subjectedto tremendous stresses. Thus, materials such as polycrystalline diamondand stainless steel are generally required. High pressure homogenizersutilize high shear to create small particles. The technologies describedhereinabove require multi-step processes and are energy intensive. Suchtechnologies require first mixing all of the ingredients with arelatively low energy device and then processing with a high pressurehomogenizer of a cavitation device several times, until the productquality is achieved.

Beyond mixing-related issues, a large number of compounds withpotentially high pharmacological value fail to pass initial screeningtests because such compounds are too hydrophobic to be effectivelyformulated. Most formulation strategies aim at increasing thebioavailability of such drugs by particle size reduction, as describedextensively in the literature. Such strategies include the production ofemulsions, liposomes and functionalized chaperones by high shearprocessing, the production of nanosuspensions by milling, micronizationor high shear processing, and the production of nanoporous materials.

Nano-emulsions, liposomes and other generalized cargo loaded systems canonly encapsulate a limited amount of drug. Therefore, current approachesmay not be the strategies of choice for drugs with high dosage demands.Nanosuspensions can deliver much larger amounts of drug in a smallervolume than solvent-diluted drug systems and, therefore, may have apotential advantage as a formulation strategy when a high dose isrequired. Further, these conventional methods have high energy demandsand are multi-step.

Most often, nanosuspensions are produced by milling, micronizing or highshear processing. Thus, current methods for manufacturingnanosuspensions primarily rely on the reduction of particle size of drugpowders in dry or wet formulations. Such “top-down” processes aregenerally slow, require repetitive processing cycles, and requiresubstantial energy. Indeed, the targeted particle sizes, usually lessthan 0.5 microns, are often time consuming and expensive to produce,frequently requiring repetitive processing cycles/passes through themilling/high shear equipment to achieve desired particle sizedistributions.

Controlled crystallization of drugs is an alternative to the productionof drug nanosuspensions through size reduction techniques for generatingdesired particle size distributions. Crystallization is a method that isused to produce fine chemicals and pharmaceuticals of desired purityand/or for the formation of a specific crystal polymorph with desiredcrystalline structure and associated properties. However, currentcrystallization techniques typically produce particles in the range ofseveral microns which are not suitable for delivering highly hydrophobicdrugs. More recently, methods for production of nanosuspensions throughcrystallization have been proposed, but they have not demonstrated thenecessary productivity robustness. In particular, the newer procedureslack the control that is required at the various mechanistic steps ofcrystallization (nucleation rate through crystal morphology andstabilization), process scalability and general applicability.

The patent literature describes processing equipment for particle sizecontrol and manipulation. For example, commonly assigned U.S. Pat. Nos.4,533,254 and 4,908,154 to Cook et al. describe processing systems andapparatus having particular utility in emulsion and microemulsionprocessing. Flow streams are forced under pressure to impinge in alow-pressure turbulent zone. The disclosed systems/apparatus include aplurality of nozzles that effect impingement of flow sheets along acommon liquid jet interaction front.

Greenwood et al. disclose a sterilizable particle-size reductionapparatus in WO 2005/018687. Kipp et al. disclose methods/apparatus forgenerating submicron particle suspensions that involves mixing asolution that contains a pharmaceutically active compound that isdissolved in a water-miscible solvent with a second solvent to form apre-suspension of particles and then energizing the mixture to form aparticle suspension having an average particle size of less than 100 μm(see U.S. Patent Publications 2003/0206959 and 2004/0266890; U.S. Pat.No. 6,977,085).

In the field of crystallization, the patent literature includes variousteachings from the pharmaceutical industry. For example, U.S. Pat. No.5,314,506 to Midler, Jr. et al. discloses the use of impinging jets toachieve high intensity micromixing of fluids so as to form a homogeneouscomposition prior to the start of nucleation in a continuouscrystallization process. Nucleation and precipitation are initiated byutilizing the effect of temperature reduction on the solubility of thecompound to be crystallized in a particular solvent (thermoregulation),or by taking advantage of the solubility characteristics of the compoundin solvent mixtures, or a combination thereof. U.S. Pat. No. 5,578,279to Dauer et al. discloses a dual jet crystallizer apparatus thatincludes a crystallization or mixing chamber having opposed angularlydisposed jet nozzles. The nozzles deliver the compound to becrystallized and a crystallization agent. U.S. Pat. No. 6,558,435 to AmEnde et al. discloses a process for synthesis/crystallization of apharmaceutical compound that involves contacting diametrically opposedliquid jet streams, such that the liquid streams meet at a point ofimpingement to create a vertical impingement film and create turbulenceat their point of impact under conditions of temperature and pressurewhich permit reaction of reactive intermediates to produce a product.The jet streams are disclosed to have sufficient linear velocity toachieve micromixing of the jet stream constituents, followed by reactionand nucleation to form high surface area crystals. See also U.S. PatentPublication No. 2006/0151899 to Kato et al.

More recently, U.S. Pat. Nos. 8,187,554 and 8,367,004 to Panagiotou etal. describe apparatus, systems, and methods for achieving interactionof constituents within an interaction chamber to promote mixing and/orreaction phenomena. Unfortunately, however, the apparatus, systems, andmethods disclosed in the '554 and '004 patents have significantshortcomings. One shortcoming is such apparatus, systems, and methodsresult in a nano- or micro-particle formulation having incorrectproportions of constituents. The apparatus, systems, and methods of the'554 and '004 patents describe two feed streams that are directly fed toan intensifier pump at different individually actively controlled ratessuch that interaction between the two feed streams is substantiallyprevented prior to pressurization within the intensifier pump, thereby,avoiding potential reactions and other constituent interactions prior tomicro- and/or nano-scale interactions within the interaction chamberdescribed therein. Thus, such a system uses a first pump to control afirst feed stream, a second pump to control a second feed stream, and anintensifier pump to control the mixture of first feed stream and thesecond feed stream (i.e., the inputs and outputs are being controlled).In theory, it would seem advantageous to actively control the flow rateof the system by actively controlling each feed stream (e.g., attemptingto have each feed stream enter the system, flow through the system, andexit the system at the same flow rate). However, in practice, it is verydifficult and, in most applications, not possible to control enoughequipment and processes in the system to achieve such a sufficient flowrate. Such difficulties arise because the flow rates are pulsatingrather than being completely constant, which results in a sufficientflow rate not being achieved. In such a system, the flow rate is aprocessing rate that is too low or too high. Such an insufficient flowrate results in a disruption of the desired ratio of the constituents ofthe feed streams and ultimately failure to achieve the desired micro-and/or nano particle formulation. Additionally, a lack of control of theflow rate of the system can make scale up very problematic.

Another shortcoming is that a primary goal of the apparatus, systems,and methods disclosed in the '554 and '004 patents is to keep the firstand second feed streams separate until entering an intensifier pump(i.e., to prevent pre-mixing of the first and second feed streams). Thefirst and second feed streams mix when such streams enter theintensifier pump. However, it is difficult, and in many cases notpossible, to control the mixing in the intensifier pump. Such a lack ofcontrol results in the creation of blobs of constituents, especially ifthe constituents consist of immiscible liquids. This is a significantproblem because reaction chambers have very small internal volume. In anexample involving water and oil, blobs of only water or only oil mayflow from an intensifier pump to a reaction chamber. However, ahomogenous mixture of oil and water in a particular ratio wouldgenerally be desired. If the system passes blobs of oil and/or waterthrough the reaction chamber, the resulting micro- or nano-particleswill be too large and will not have the desired ratio. The lowprocessing rates of the system will also lead to the blobs plugging themicrochannels in the reaction chamber, which would make such a systemunsuitable for large scale production, especially in the chemical andpharmaceutical industries.

A further shortcoming is that the apparatus, systems, and methodsdisclosed in the '554 and '004 patents provide insufficient time toachieve certain desired processes and chemical reactions. For example,the first and second feed streams only pass through an intensifier pumpand a reaction chamber. A typical residence time for an intensifier pumpis commonly about 1 or 2 seconds but a process may require as high asabout 40 seconds. A common residence time for a reaction chamber isabout 1 millisecond. Given such a minimal time frame to conduct aprocess in the apparatus, systems, and methods disclosed in the '554 and'004 patents, many desirable processes and chemical reactions thatrequire more time would not be possible.

Despite efforts to date, a need remains for systems/apparatus andmethods that are effective in producing nanoparticles. Systems/apparatusand processes for generation of nanoparticles in an efficient,continuous and reliable manner are also needed. Beyond nanoparticleprocessing, there remains a need for systems/apparatus and methods thatare effective in facilitating various materials processing operations,e.g., reaction, emulsion and/or crystallization processes, by, interalia, minimizing diffusion limitations to requisite interaction betweenreactants and/or crystallizing constituents. Still further, a needremains for systems and methods that yield desirable particle sizedistributions, morphology and/or compositions/phase purities througheffective process design and/or control. Indeed, a need remains forsystems and methods that effectively control interfacialreaction/contact between constituents to achieve desired processingresults, e.g., to reduce the potential for undesirable side reactions.

SUMMARY

The present disclosure addresses the problems described above byproviding the disclosed systems/apparatus and methods for continuouslyprocessing at least two liquid feed streams. One aspect of the presentdisclosure provides a method for continuously processing at least twoliquid feed streams. In some embodiments, the method comprises: pumpinga first feed stream to an in-line mixer at an actively automaticallycontrolled rate; flowing a second feed stream to the in-line mixer;mixing the first and second feed streams to achieve a substantiallyhomogeneous mixture; pumping the substantially homogeneous mixture to ahigh pressure pump at an actively controlled rate; pressurizing thesubstantially homogeneous mixture within the high pressure pump to anelevated pressure of at least 35 MPa; and delivering the substantiallyhomogeneous mixture to a microreactor downstream from the high pressurepump. In some embodiments, the microreactor has a minimum channeldimension of 500 microns or less, causing the first and second liquidstreams to interact within the microreactor at a nanoscale level.

In some embodiments, the first feed stream includes a first constituentand the second feed stream includes a second constituent. In someembodiments, the first and second feed streams are delivered to thein-line mixer in feed lines that are coaxially aligned. In someembodiments, the first and second feed streams are introduced to thein-line mixer through spaced ports defined by the in-line mixer. In someembodiments, the actively controlled rate for delivery of the first feedstream to the in-line mixer is effected by an actively controlled feedpump for the first feed stream. In some embodiments, the method furthercomprises cooling or quenching the substantially homogenous mixtureafter interaction within the microreactor.

In some embodiments, the first constituent includes a solvent and thesecond constituent includes an antisolvent. In some embodiments,interaction of the solvent and the antisolvent in the microreactor iseffective to define a nanosuspension. In some embodiments, the methodfurther comprises obtaining constituent nanoparticle crystals from thenanosuspension. In some embodiments, the solvent stream is selected fromthe group consisting of dimethyl sulfoxide (DMSO),N-Methyl-2-Purrolidone (NMP), methanol, ethanol, acetone,dichloromethane, octanol and isopropyl alcohol. In some embodiments, theantisolvent stream is selected from the group consisting of water,hexane and heptane. In some embodiments, the solvent stream is DMSO andnanoparticles of azithromycin are obtained at a median particle size ofabout 50-100 nm. In some embodiments, the solvent stream is DMSO andnanoparticles of oxycarbazepine are obtained at a median particle sizeless than 1000 nm. In some embodiments, the solvent stream is DMSO orNMP and nanoparticles of loratadine are obtained at a median particlesize of less than 500 nm. In some embodiments, the method furthercomprises cooling or quenching the nanosuspension after interactionwithin the microreactor.

In some embodiments, the elevated pressure is at least about 70 MPa. Insome embodiments, the elevated pressure is at least about 140 MPa. Insome embodiments, the elevated pressure is at least about 207 MPa. Insome embodiments, the ratio of the flow rate of the second stream to theflow rate of the first stream is at least about 2:1. In someembodiments, the ratio of the flow rate of the second stream to the flowrate of the first stream is at least about 3:1. In some embodiments, theratio of the flow rate of the second stream to the flow rate of thefirst stream is at least about 10:1.

In some embodiments, the microreactor has channels with minimumdimensions in the range of 10-500 microns. In some embodiments, theaverage fluid velocity in microreactor channels is in the range of300-500 m/s. In some embodiments, the method further comprises effectinga sheer rate in the microreactor of at least about 1.2×10⁶ s⁻¹. In someembodiments, the microreactor has a single slot geometry.

In some embodiments, at least one of the liquid feed streams includessolid particles. In some embodiments, at least one of the feed streamscontains seed particles. In some embodiments, at least one of the feedstreams contains catalyst particles. In some embodiments, the firstconstituent is a first reactant and the second constituent is a secondreactant. In some embodiments, the method further comprises adjustingreaction selectivity by controlling interaction between the first andsecond reactants prior to the nanoscale level interaction within themicroreactor. In some embodiments, control of the interaction betweenthe first and second reactants is effected by encouraging contactbetween the first and second reactants in the in-line mixer prior topressurization in the high pressure pump so as to achieve thesubstantially homogeneous mixture. In some embodiments, thesubstantially homogeneous mixture is pumped to the high pressure pumpthrough a port defined by the high pressure pump. In some embodiments,the method further comprises cooling or quenching the substantiallyhomogeneous mixture after reaction within the microreactor.

In some embodiments, the first and second feed streams are immiscible.In some embodiments, the first and second feed streams are miscible. Insome embodiments, the constituents interact within the microreactor toachieve an emulsion, a dispersion, a liposomal formulation, lipidnanoparticles, or a crystalline or amorphous material. In someembodiments, the first feed stream is an oil phase and the second feedstream is a water phase. In some embodiments, the oil phase is selectedfrom a vegetable oil, a nut oil, an animal oil, an inorganic oil, alipid, a surfactant, a polymer, an active ingredient, a flavoring, acoloring, an alcohol, an organic solvent, and/or a derivative thereof.In some embodiments, the water phase is selected from water, lipid,surfactant, viscosity modifier, pH adjuster, and sugar. In someembodiments, the first feed stream is a water phase and the second feedstream is an oil phase. In some embodiments, the oil phase is selectedfrom a vegetable oil, a nut oil, an animal oil, an inorganic oil, alipid, a surfactant, a polymer, an active ingredient, a flavoring, acoloring, an alcohol, an organic solvent, and/or a derivative thereof.In some embodiments, the water phase is selected from water, lipid,surfactant, viscosity modifier, pH adjuster, and sugar.

Another aspect of the present disclosure provides a system forcontinuously processing at least two liquid feed streams. In someembodiments, the system comprises a feed pump that is adapted to pump afirst feed stream downstream at an actively automatically controlledrate; an in-line mixer positioned to receive the first feed stream fromthe feed pump and a second feed stream from a feed line; a high pressurepump positioned to receive the substantially homogeneous mixture fromthe in-line mixture; and a microreactor downstream of the high pressurepump. In some embodiments, the in-line mixer is adapted to mix the firstand second feed streams to achieve a substantially homogeneous mixture.In some embodiments, the microreactor has a minimum channel dimension of500 microns or less. In some embodiments, the microreactor is adapted toeffect high shear fields so as to achieve thorough mixing of thesubstantially homogeneous mixture.

In some embodiments, the feed pump is a metering pump. In someembodiments, the first and second feed streams are delivered to thein-line mixer in a coaxial arrangement. In some embodiments, themicroreactor has a single slot geometry. In some embodiments, the systemfurther comprises a cooling unit downstream of the microreactor. In someembodiments, the in-line mixer includes a plurality of spaced feedports. In some embodiments, the first feed stream is introduced to thein-line mixer through a first feed port and the second feed stream isintroduced to the in-line mixer through a second feed port.

In some embodiments, the first feed stream includes a first constituentand the second feed stream includes a second constituent. In someembodiments, the microreactor is adapted to effect a controllednanoscale interaction between the first constituent and the secondconstituent. In some embodiments, the microreactor is adapted to effectinteraction of a first reactant in the first feed stream and a secondreactant in the second feed stream at a nanoscale level. In someembodiments, the system is configured so that reaction selectivity canbe controlled by controlling interaction between the first and secondreactants prior to the nanoscale level interaction within themicroreactor. In some embodiments, control of the interaction betweenthe first and second reactants is effected by encouraging contactbetween the first and second reactants in the in-line mixer prior topressurization in the high pressure pump so as to achieve thesubstantially homogeneous mixture. In some embodiments, the first andsecond reactants are delivered to the in-line mixer through spaced portsdefined by the in-line mixer.

In some embodiments, the elevated pressure is at least about 70 Mpa. Insome embodiments, the elevated pressure is at least about 140 MPa. Insome embodiments, the elevated pressure is at least about 207 MPa.

In some embodiments, the ratio of the flow rate of the second stream tothe flow rate of the first stream is at least about 2:1. In someembodiments, the ratio of the flow rate of the second stream to the flowrate of the first stream is at least about 3:1. In some embodiments, theratio of the flow rate of the second stream to the flow rate of thefirst stream is at least about 10:1.

In some embodiments, the microreactor has channels with minimumdimensions in the range of 10-500 microns. In some embodiments, theaverage fluid velocity in microreactor channels is in the range of300-500 m/s. In some embodiments, the sheer rate effected in themicroreactor is at least about 1.2×10⁶ s⁻¹. In some embodiments, themicroreactor has a single geometry.

Micro-scale apparatus, systems and methods are provided according to thepresent disclosure that facilitate and utilize microreactor technologyto achieve desired mixing and interaction at a micro and/or molecularlevel between and among feed stream constituents. The disclosedapparatus, systems and methods are capable of various degrees of mixingintensity and control of energy dissipation mechanisms, therebymaximizing useful work in forming surfaces and interfaces between andamong constituent molecules/compounds. The present disclosure permitsadvantageous reductions in system entropy that might be otherwiseexperienced due to process inefficiencies. Such entropy reduction is amajor benefit standing alone, but also translates to minimizing energylost to heat, sound, light and cavitation. Indeed, reduced systementropy advantageously further translates to a reduced propensity forcomponent damage.

Furthermore, the disclosed apparatus, system and methods advantageouslyfacilitate and/or support process intensification, thereby miniaturizingunit operations and processes through both scale reduction andintegration of operational steps, e.g., mixing, reaction and separationunit operations. Consequently, processes utilizing the disclosedapparatus, systems and methods offer enhanced efficiency and costeffectiveness. In addition, exemplary embodiments/implementations of thedisclosed apparatus, systems and methods are adapted to function inenvironments that require portability, thereby providing enhancedflexibility in applications and in-use time.

The disclosed apparatus, systems and methods make it possible toovercome the limitations of prior art systems through precise control ofenergy input and dissipation mechanisms that dictate/control processpathways and rates. For example, in an exemplary implementation of thepresent disclosure, solvent composition may be used to affectsuper-saturation conditions, e.g., through addition of a miscible nonsolvent. In further exemplary implementations of the present disclosure,a process/method is provided that employs a solvent/anti-solventcrystallization technique in conjunction with the disclosedapparatus/system to produce advantageous drug nanosuspensions. Ascompared to micro-mixing models reported in the literature, turbulentenergy dissipation rates attainable in the disclosed reactionchambers/microreactors are on the order of 10⁷ W/kg and higher. Thedisclosed apparatus/system thus achieves rapid micro-mixing (time scale4 μs) and meso-mixing (time scale 20 μs), with a nominal residence timein the reaction chamber that is on the order of 1 ms. In addition,mixing at the nanometer scale provides a uniform supersaturation ratiowhich is a major controlling factor in crystal formation and growth.Controlling the timing and location of the mixing of the solvent andanti-solvent streams provides control of the onset of the nucleationprocess. This control, in combination with a homogeneous supersaturationratio, results in desirably uniform crystal growth and stabilizationrates.

Numerous processes may benefit through use/implementation of thedisclosed apparatus and systems. In particular, process implementationsbenefit, at least in part, based on an ability to maximize the degree towhich input energy is desirably directed to forming/establishinginteraction surfaces and interfaces. Turbulence and surface tensionforces achieved according to the present disclosure are advantageouslyeffective in initiating nano-scale events, such as formation of stablenano-emulsions and formation of sufficient molecular clustering tocreate/establish homogeneous nucleation sites for crystal growth.Exemplary applications/implementations of the present disclosure alsoinclude, but are not limited to, selectivity enhancement in competitivereaction networks, control of size of dispersed solids (whether fromreactive precipitation, crystallization and/or declustering), control ofcrystalline drug polymorph selectivity, and formation of chaperonesystems via encapsulation of active ingredients.

The foregoing phenomena are important parameters for reactions/systemsthat are limited and/or controlled by mass transfer rates/performance.Thus, the present disclosure advantageously facilitates formation ofcritical sized clusters that become homogeneous nucleation sites forcrystal growth via high degrees of local super-saturation. Suchnucleation sites influence the molecular diffusion processes formingsurfaces, their growth rates, integration of various molecular speciesinto the surface, and ultimate size and purity of the particles formed.

The foregoing molecular species may form various polymorphs, and thedesired form can be obtained through manipulation of operationalparameters, e.g., microreactor design, microreactor geometry, pressuregenerated by the high pressure pump, supersaturation ratio, solvents,antisolvents, temperature and combinations thereof. Mass transferlimitations in multiphase reacting systems can be overcome according tothe present disclosure, e.g., in the production of biodiesel, becausethe liquid reactants have limited solubility in each other and,therefore, an interfacial reaction must occur during an initial “lagphase.” The rate of such interfacial reaction may be enhanced bydispersing small droplets of one phase into the other, greatly improvingthe interfacial surface area to volume ratio.

The same phenomenon is noted when heterogeneous reactions involvingsolid particles are involved. In particular, a surface-to-volumeenhancement accelerates turnover rates proportional to surface areaavailability, whether the surface is catalytic or a reactant. Moreover,boundary layer resistances are reduced as particle size is reduced, onceagain promoting reaction rates up to their fundamental/intrinsic rates.This phenomenon is also applicable when interfacial mass transfer limitsdownstream separation processes, e.g., for downstream extraction,absorption, and adsorption processes, and for formation of stableemulsions, with or without surface active agents, since droplets at nanoscale sizes, although thermodynamically unstable, can exist for lengthytime scales due to an extremely slow kinetics response.

Chaperone systems, such as with immiscible fluids or isolationrequirements from the continuous phase (as in targeting for imagingand/or drug delivery) are readily prepared via the present disclosureusing surface active agents as the encapsulate and, due to minimizationof potential heat effects while processing vesicles, heat liable surfaceactive agents, such as those with protein functionality, can beutilized. The high shear forces associated with the disclosed reactionchambers can be beneficial when shear thinning or thickening behavior isto be exploited during processing.

In addition, the present disclosure facilitates encapsulation down tothe nano-scale of hydrophobic substances within amphi-morphicsurfactants for dispersion in hydrophilic environments (or vice versa),as in nutraceutics, pharmaceutics, and cosmetics, among others. Theencapsulates can also be useful in functionalizing membranes andproviding “smart” characteristics; for example, as (a) sequesteringagents in guard systems, (b) controlled release of growth factors intissue engineering applications, (c) soluble gas transport enhancement,and (d) in general sensor/recorder systems. The disclosedapparatus/systems and methods may be used to facilitate both fast andslow processes, and to facilitate chemical reactions and physicalprocesses, such as crystallization.

Further, the present disclosures advantageously facilitates productionof polymer nanosuspensions in the range of 50-500 nm using both emulsionand precipitation methods. By controlling processing parameters,nanosuspensions with various polymer sizes and densities may be created.The disclosed systems/methods may be used to provide activepharmaceutical ingredients (APIs) that are encapsulated or otherwisecontained within a polymeric matrix. In this sense, the polymeric matrixfunctions as a “chaperone” for such API's. The polymeric matrix isgenerally amorphous and may advantageously define a biocompatible and/orbioabsorbable product. The feedstream for such processing techniques mayinclude monomeric constituents, polymeric constituents or combinationsthereof.

Exemplary processing roadmaps for processing regimens may be developedusing the disclosed apparatus/systems. For example, roadmaps for drugcrystallization may be developed as follows: (i) determine solvent,antisolvent and surfactant constituents based on applicable inputcriteria, e.g., solubilities, toxicities, compatibility and screeningexperiments; (ii) introduce the selected solvent, antisolvent andsurfactant constituents to the disclosed apparatus/system to produceadvantageous nanosuspensions based on applicable process variables,e.g., microreactor chamber design, pressure and supersaturation ratio;and (iii) purify the nanosuspension (if required) to recovercrystallized drug, e.g., using centrifuge, filter, rinsing and/orlypholization techniques. The disclosed roadmaps may be used to yieldcrystallized particles characterized by desired particle sizes andparticle size distributions.

More generally, roadmaps may be developed and implemented for variousprocessing regimens according to the present disclosure. Exemplarymethods may involve, inter alia:

a. Identifying a solvent or first reactant/continuous phase, and anantisolvent or second reactant/dispersed phase which together define aprocess stream;

b. Determining need for surfactant(s) to achieve desiredstability/control of process stream;

c. Determining concentration of target molecule/species or reactantswithin solvent or process stream/dispersed phase, and ratio ofsolvent/antisolvent or reactants/continuous phase/dispersed phase toachieve a predetermined level of supersaturation or contactefficiency/efficacy to drive relevant mechanism, e.g., crystallizationmechanism, reaction mechanism, emulsion mechanism, coating mechanism,etc.;

d. Introducing predetermined amount(s) of energy to the process stream;

e. Regulating energy dissipation mechanism(s) at specified locationswithin system;

f. Contacting the solvent/antisolvent, reactants or continuous/dispersedphases in a confined volume at a nanoscale so as to deliver product of adesired characteristic, e.g., products having a desired particle sizedistribution, morphology, composition and/or combinations thereof.

The present disclosure provides other advantages compared to otherapproaches in the art that have been utilized. One advantage of theapparatus, systems and methods according to some embodiments is thatsuch apparatus, systems and methods yield high accuracy of the desiredflow rates of each stream and the flow rate ratio of the two streamscombined with the ability to adjust the flow rates and the flow rateratio of the two streams in real time, which results in a micro- ornano-particle having the desired formulation. An advantage according toanother embodiment is the ability to vary the residence times andtherefore the interaction time of the two streams at will, which makesthe system suitable for processes that require long interaction (tens ofseconds) and for processes that required shorter interactions (fewerthan ten seconds). An advantage according to another embodiment is thathomogenous material entering the microreactor results in processestaking place under uniform conditions. Therefore, the final product isuniform in terms of particle size, particle composition, and structure.All of the advantages described in the present disclosure improve theability to scale up the process, while maintaining the desired flowrates, flow rate ratios, and uniform conditions in the production of thefinal product.

Additional advantage features, functions and implementations of thedisclosed apparatus, systems and methods will be apparent from thedescription which follows, particularly when read in conjunction withthe appended figures.

BRIEF DESCRIPTION OF THE FIGURES

The above-mentioned aspects of embodiments will become more apparent andwill be better understood by reference to the following description ofthe embodiments taken in conjunction with the accompanying drawings,wherein:

FIG. 1 shows a system for continuously processing at least two liquidfeed streams in accordance with an embodiment of the present disclosure;

FIG. 2 shows a system for continuously processing at least two liquidfeed streams in accordance with an embodiment of the present disclosure;

FIG. 3 shows a system for continuously processing at least two liquidfeed streams in accordance with an embodiment of the present disclosure;

FIG. 4 shows an in-line mixer in accordance with an embodiment of thepresent disclosure;

FIG. 5 shows an in-line mixer in accordance with an embodiment of thepresent disclosure;

FIG. 6 shows a system for continuously processing at least two liquidfeed streams in accordance with an embodiment of the present disclosure;

FIG. 7 shows a microreactor in accordance with an embodiment of thepresent disclosure;

FIG. 8 shows a system for continuously processing at least two liquidfeed streams in accordance with an embodiment of the present disclosure;and

FIG. 9 shows a system for continuously processing at least two liquidfeed streams in accordance with an embodiment of the present disclosure.

DETAILED DESCRIPTION

The present disclosure provides advantageous systems and methods forachieving effective contact/interaction of constituents within a definedchamber, i.e., a microreactor, to enhance and/or promote a host ofmixing and/or reaction phenomena. Set forth herein below aredescriptions of exemplary system designs and implementations, includingexemplary implementations and beneficial results achieved thereby.Although the systems and methods of the present disclosure are describedwith reference to exemplary embodiments and implementations, it is to beunderstood that the present disclosure is not limited to suchillustrative examples. Rather, the disclosed apparatus, systems andmethods may take various physical forms and be applied to a multitude ofprocessing schemes and environments, without departing from the spiritor scope of the present disclosure.

A. Exemplary Apparatus/System Design(s) and Exemplary Methods

Referring now to FIG. 1, an illustrative system 100 for continuouslyprocessing at least two liquid feed streams in accordance with thepresent disclosure is schematically depicted. System 100 includesholding tank 102 and holding tank 104. In some embodiments, holding tank102 and holding tank 104 are optional equipment. Holding tank 102 isadapted to hold a first liquid stream 130. Holding tank 104 is adaptedto hold a second liquid stream 132. Holding tank 102 is connected to apump 106 via a first feed line 108. In some embodiments, pump 106 is ametering pump, positive displacement pump, syringe pump, peristalticpump, or piston pump. Pump 106 is connected to a first port 110 of anin-line mixer 112 via the first feed line 108. Holding tank 104 isconnected to a second port 114 of an in-line mixer 112 via a second feedline 116.

In-line mixer 112 includes first port 110 and second port 114. In-linemixer 112 also includes mixing elements 118. In some embodiments, thein-line mixer is a T-mixer, a static mixer with baffles, a rotor-statormixer, a propeller mixer, a co-axial orifice or an ultrasonic mixer, toname a few. Such in-line mixers have a variety of energy levels andmixing intensity. In-line mixer 112 is connected to a high pressure pump(not shown) via a conduit 122. High pressure pump (not shown) isconnected to a microreactor 120 via a conduit 122. Microreactor 120 isconnected to a heat exchange unit 124 via conduit 126. Heat exchangeunit 124 is connected to a collection tank 128 via conduit 126. In someembodiments, the heat exchange unit 124 is optional equipment. In someembodiments, the microreactor 120 includes a heat exchange unit (notshown), and, in such embodiments, the heat exchange unit 120 would beunnecessary.

In the illustrative embodiment, pump 106 is capable of pumping firstliquid stream 130 downstream to first port 110 of the in-line mixer 112via first feed line 108. In some embodiments, the pumping moves aprecise volume of first liquid stream 130 in a specified time periodproviding an accurate volumetric flow rate. In some embodiments, pump106 is utilized to pump first liquid stream 130 downstream to in-linemixer 112 at an actively automatically controlled rate. In someembodiments, the actively automatically controlled rate is achievedbased on operation of the individually controlled pump 106. Secondliquid stream 132 flows downstream through the second port 114 viasecond feed line 116. In some embodiments, the flow rate of the secondliquid stream 132 is controlled indirectly by the pumping action of themicroreactor 120. The first liquid stream 130 and the second liquidstream 132 may take various forms and exhibit various propertiesaccording to the present disclosure. In some embodiments, the firstliquid stream 130 and the second liquid stream 132 may be multiphasefluids, miscible fluids, or immiscible fluids. In some embodiments, thefirst liquid stream 130 and the second liquid stream 132 may containparticles and or may contain constituents that react with each other. Insome embodiments, the manner in which the first liquid stream 130 andthe second liquid stream 132 are processed and/or stored prior tointroduction to system 100 may vary widely, with the disclosedreservoirs and feed lines being merely illustrative of pre-processinghandling/storage of reactant/fluid streams. In some embodiments, a pump(not shown) is used to deliver the second liquid stream 132 downstreamthrough the second port 114. First liquid stream 130 and second liquidstream 132 each have a pre-determined flow rate and composition. In someembodiments, the pump 106 is used to adjust the flow rate of the firstliquid stream 130. In some embodiments, a valve or orifice (not shown)is used to adjust the flow rate of first liquid stream 130 and/or secondliquid stream 132.

First liquid stream 130 and second liquid stream 132 mix in the in-linemixer 112 to form a substantially homogeneous mixture 134. As usedherein, the term “substantially homogeneous mixture” means a mixture oftwo liquid streams that has the same or substantially similar proportionof its constituents throughout any given sample of the mixture. Forexample, when dividing the volume of a mixture of two liquid streams inhalf, the same or substantially similar amount of constituents arepresent in each half. In some embodiments, the composition of theconstituents in the mixture of the two liquid streams may fluctuateslightly above or below the average composition of the constituents inthe mixture.

The function of the in-line mixer is two-fold: (a) it forms asubstantially homogeneous mixture 134 that can be introduced into themicroreactor 120 and mixed further, and (b) various processes that startin the in-line mixer (i.e., crystallization, chemical reactions, etc.)have enough time to reach the desired state of completion at the exit ofthe microreactor 120. Generally, the in-line mixer 112 does not providehigh enough energy to create nanoparticles 136; however, themicroreactor 120 is employed to create nanoparticles 136. Therefore, thesubstantially homogenous mixture 134 is processed by the microreactor120 since the microreactor 120 generates turbulent flow fields that haveturbulent eddies as low as 20 nm. If the first liquid stream 130 andsecond liquid stream 132 contain species that react with each other,chemical reactions may take place inside these eddies resulting innanometer size particles. If the first liquid stream 130 and secondliquid stream 132 are immiscible, one of the liquid streams 130 or 132may form nanosized droplets that are dispersed in the other liquid. Ifsurfactants are used, the droplets may be stabilized formingnanoemulsions with a long shelf life.

In some embodiments, in-line mixer 112 is replaced with a tube (notshown) of sufficient length inside which the first liquid stream 130 andthe second liquid stream 132 may mix to form a substantially homogenousmixture 134. In such embodiments, the mixing is the result of moleculardiffusion and/or turbulence. In some embodiments, the time required forcomplete mixing may be calculated as a result of velocities in the tube,the type of flow in the tube (turbulent or laminar, single phase ormultiphase), the dimensions of the tube, the diffusivity of the speciesand other physical properties, as well the pressure and temperature.

In the illustrative embodiment, the substantially homogeneous mixture134 is pumped downstream from the in-line mixer 112 to the high pressurepump (not shown) via conduit 122. The high pressure pump is generallyeffective to pressurize the substantially homogenous mixture 134 to anelevated pressure, e.g., a pressure of up to 40,000 psi. As used herein,the term “high pressure pump” refers to a high pressure pump that isadapted to deliver high pressure output streams, e.g., 500 to 40,000 psiand higher. In some embodiments, the high pressure pump is anintensifier pump or a piston. An exemplary high pressure pump accordingto an embodiment includes a hydraulic pump and a piston that multipliesthe system pressure therewithin. Thus, in such embodiment, the hydraulicpump may be effective to generate pressures of about 1500 to 3500 psi,and the piston mechanism may be effective to multiply such pressure by afactor of 10× to 30×. Each piston within a pressure assembly may beviewed as a distinct high pressure pump for purposes of the presentdisclosure. Exemplary high pressure pumps according to some embodimentsof the present disclosure avoid cavitation, thereby minimizing potentialenergy dissipation associated therewith.

The substantially homogeneous mixture 134 is pumped downstream from thehigh pressure pump (not shown) to the microreactor 120 via conduit 122.The pumping action of the microreactor 120 pulls the second liquidstream 132 into the in-line mixer 112 (i.e., causes the flow of thesecond liquid stream 132 into the in-line mixer 112). In someembodiments, the microreactor 120 includes a pump (not shown) thatmaintains a certain pressure at a port (not shown) of the microreactor120.

In some embodiments, the microreactor 120 is any commercial highpressure homogenizer, including, without limitation, with fixed geometrysuch as Microfluidics (Westwood, Mass., USA), DyHydromatics (Maynard,Mass., USA) and BEEI (South Easton, Mass., USA); valve homogenizers suchas Niro Soavi (Parma, Italy), APV (PPXFLOW/United Kingdom) and Avestin(Canada). High-pressure homogenizers are high energy level mixingdevices and are, therefore, capable of producing nanoparticles. In theillustrative embodiment, microreactor 120 produces nanoparticles 136.The various homogenizers have different characteristics that make themsuitable or unsuitable for different applications.

The nanoparticles 136 flow from the microreactor 120 to the heatexchange unit 124 via conduit 126. The heat exchange unit 124 isutilized to cool the nanoparticles 136. Nanoparticles 136 flow from heatexchange unit 124 to the collection tank 128 via conduit 126. Mixinghighly affects the rates of phenomena that are responsible for formingthe nanoparticles 136, including precipitation, crystallization,emulsification, or chemical reactions. These processes should becompleted at the exit of the microreactor 120. If such processes are notcompleted at the exit of the microreactor 120, the nanoparticles 136will continue to grow uncontrollably after the microreactor 120. Toachieve completion of the intended process, the first liquid stream 130and second liquid stream 132 should have sufficient contact time priorto being processed within the microreactor 120, which is facilitated bycontrolling the homogeneity of the mixture of the two liquid streams 130and 132 via the in-line mixer 112 and the dimensions of the conduit 122between the in-line mixer 112 and the microreactor 120.

In the illustrative embodiment, the pump 106 in combination with thehigh pressure pump (not shown) control the flow rate ratios of the twostreams. The energy input to the fluid at different locations of thesystem is controlled by the geometry of the flow path. Thus, energydissipation may be controlled/minimized through advantageous pipingdesign/layout, the design/geometry of the microreactor 120, and thedesign/layout of heat exchange unit 124 positioned downstream of themicroreactor 120. Typically, energy dissipation is most stronglyinfluenced by the design/geometry of the microreactor 120, e.g., throughturbulence and/or shear associated therewith.

Referring now to FIG. 2, an illustrative system 200 for continuouslyprocessing at least two liquid feed streams in accordance with thepresent disclosure is schematically depicted. In-line mixer 112 isconnected to conduit 122. Conduit 122 connects to conduit 204. Conduit204 connects to overflow tank 202. In the illustrative embodiment,overflow tank 202 may optionally be located before and/or after thein-line mixer 112. In some embodiments, the overflow tank 202 isemployed to ensure that both the in-line mixer 112 and the microreactor120 operate at capacity. In some embodiments, some amount ofsubstantially homogeneous mixture 134 flows into overflow tank 202 fromconduit 122 via conduit 204.

Referring now to FIG. 3, an illustrative system 300 for continuouslyprocessing at least two liquid feed streams in accordance with thepresent disclosure is schematically depicted. Pump 106 is connected tofirst port 110 of an in-line mixer 112 via first feed line 108. A checkvalve 302 is positioned on first feed line 108 between pump 106 andin-line mixer 112. Second feed line 116 is connected to second port 114of in-line mixer 112. A check valve 304 is positioned on the second feedline 116 before the second port 114 of in-line mixer 112. In-line mixer112 is connected to microreactor 120 via a conduit 122. A check valve306 is positioned on conduit 122 between in-line mixer 112 andmicroreactor 120. Check valves 302, 304, and 306 are used to preventbackflow of the first liquid stream 130, the second liquid stream 132,and/or the substantially homogeneous mixture 134. In some embodiments,check valves 302, 304, and 306 are optional equipment.

Referring now to FIG. 4, an illustrative in-line mixer 400 in accordancewith the present disclosure is schematically depicted. The in-line mixer400 includes baffles 402. In some embodiments, the baffles 402 areemployed in the in-line mixer 400 to increase the contact area forinteraction between the first liquid stream 130 and the second liquidstream 132. In some embodiments, the baffles 402 are utilized to achievedesired hydrodynamic profiles, stress levels, and heat transfer asrequired by the system of the present disclosure.

Referring now to FIG. 5, an illustrative in-line mixer 500 in accordancewith the present disclosure is schematically depicted. In-line mixer 500is a T-mixer. First liquid stream 130 is pumped to first port 110 of thein-line mixer 500. Second liquid stream 132 flows to second port 114 ofthe in-line mixer 500. The first liquid stream 130 and second liquidstream 132 enter the in-line mixer 500 via the first port 110 and secondport 114, respectively. In-line mixer 500 mixes the first liquid stream130 and the second liquid stream 132 to form a substantially homogeneousmixture 134.

Referring now to FIG. 6, an illustrative system 600 for continuouslyprocessing at least two liquid feed streams in accordance with thepresent disclosure is schematically depicted. Pump 106 is connected to afirst port 606 of a co-axial orifice 602 via the first feed line 108.The co-axial orifice 602 includes a first co-axial tube 610 and a secondco-axial tube 612. The second feed line 116 is connected to a secondport 608 of the co-axial orifice 602. First co-axial tube 610 and secondco-axial tube 612 connects to third port 614 of the in-line mixer 604.In-line mixer 604 includes third port 614.

First liquid stream 130 is pumped to first port 606 of a co-axialorifice 602 via first feed line 108. Second liquid stream 132 flows tosecond port 608 of the co-axial orifice 602 via second feed line 116.The first liquid stream 130 and second liquid stream 132 enter theco-axial orifice 602 via the first port 606 and second port 608,respectively. The first liquid stream 130 enters first co-axial tube610, and the second liquid stream 132 enters the second co-axial tube612. While in the first co-axial tube 610 and second co-axial tube 612,first liquid stream 130 and second liquid stream 132, respectively, areflowing separately from each other. After first liquid stream 130 andsecond liquid stream 132 enter the in-line mixer 604 via third port 614,in-line mixer 604 mixes the first liquid stream 130 and the secondliquid stream 132 to form a substantially homogeneous mixture 134. Incomparison to the microreactor (not shown), in-line mixer 604 has lowerenergy levels by orders of magnitude.

In some embodiments, various components/equipment of the systems of thepresent disclosure may be controlled by a control system that includes acontroller having one or more processors and one or more memory devices.In some embodiments, the one or more memory devices may includeinstructions stored therein that are executable by the one or moreprocessors to control various functions and activities performed by thesystems of the present disclosure.

Referring now to FIG. 7, an illustrative microreactor 700 in accordancewith the present disclosure is schematically depicted. The microreactor700 includes a pumping mechanism that generates high pressures, in thethousands or tens of thousands of psi. As used herein, the term“microreactor” is synonymous with “reaction chamber,” “interactionchamber,” and “processing module.” The microreactor 700 also includes aprocessing module that contains passages with small dimensions,typically 10-5000 microns. There are a variety of pumping systems thatmay be utilized in microreactor 700, differing in the design andprincipal of operation. The geometry of the microreactor 700 may takevarious forms to effect the desired shear field and/or shear force. Forexample, the microreactor 700 may be characterized by (i) a “Z” or “L”type single slot geometry, (ii) a “Y” or “T” type single slot geometry,(iii) a “Z” or “L” type multi-slot geometry; or (iv) a “Y” or “T” typemulti-slot geometry. The terms “Z” type and “Y” type refer toMicrofluidics' reaction chamber geometries. The terms “L” type and “T”type refer to DyHydromatics' (Maynard, Mass.) reaction chambergeometries. Each of the foregoing microreactor geometries is known inthe art and is generally adapted to provide a high shear field forinteraction between the reactants/constituents introduced thereto. Themicroreactor 700 has an internal volume that is on the scale of amicroliter, and average velocities in the microchannels may reach and/orexceed 500 m/s. Changes in velocity magnitude and/or directionassociated with the microreactor 700 yields substantially uniform, highshear fields. The high turbulence achieved in the disclosed reactionchambers/microreactors advantageously facilitates mixing/contact at thenanometer level. The disclosed microreactor 700 is generally effectiveto generate nanoscale mixing, tight particle size distributions, andhigh levels of repeatability/scalability.

Fixed geometry homogenizers are known to produce materials with smallerparticle size and narrower particle size distribution than the size ofmaterial produced with valve homogenizers. However, the contact times offluids in valve homogenizers are generally shorter than those in fixedgeometry homogenizers. Therefore, relatively fast processing may benefitfrom valve homogenizers in addition to minimizing the dimensions of theconduit between the in-line mixer and the homogenizer. The reason forthis difference is the different pumping mechanism to produce highpressure that these homogenizers use. The fixed geometry homogenizerstypically use constant pressure pumping mechanisms. These areplungers/intensifiers that first compress the fluid and then pump itthrough the processing module. Therefore, the flow through eachintensifier is intermittent and the contact times of the fluids arerelatively long. However, the valve homogenizers use constant volumepumping mechanisms. These are high pressure pumps and produce continuousflows through the homogenizers, and the resulting residence times arerelatively short.

There are processing modules that enhance mixing of immiscible fluidswhile others enhance the shearing of solid particles. Additionally,there are processing module configurations that allow cavitation of thefluids while there are those that suppress cavitation. Therefore, foremulsions one may select processing modules that enhance the mixing ofimmiscible fluids. Processing module configurations that allowcavitation may be damaging to sensitive materials such as biologics;therefore, such configurations should be avoided in such applications.

Several parameters of the system can be controlled to produce tailorednanoparticles with desired properties according to some embodiments ofthe present disclosure, including, without limitation:

-   -   The particle size of the substantially homogenous mixture        depends on the turbulent energy dissipation rate (turbulent        mixing intensity) of the in-line mixer. Each type of mixer has        its own intrinsic rate, which may be further controlled by        adjusting the operational parameters of the in-line mixer. Such        operational parameters include the geometry of the in-line mixer        and the flow rates of the individual liquid streams.    -   The geometry of the conduit between the in-line mixer and the        microreactor affects the contact time of the liquid streams.        Slow processes require longer times and therefore longer        conduits than faster processes.    -   Additionally, the internal geometries of the in-line mixer and        microreactor also affect the contact times.    -   The microreactor highly influences the final particle size        through (i) the pressure, which is a measure of the energy        imparted on the fluid, and (ii) the geometry of the processing        module of the microreactor. The processing module of the        microreactor has various names, depending on the type of the        device and the manufacturer. For example, in valve homogenizers        the processing module is named a homogenizing valve.        Microfluidics names its processing modules interaction chambers        while DyHydromatics names their processing modules reaction        chambers. Another name commonly used to describe the processing        module is a microreactor.    -   The temperature of the fluids throughout the system influences        the final product.

The types of materials that can be produced by the apparatus, systems,and methods of the present disclosure include nanoemulsions,nanodispersions, liposomes (semi-solids), lipid nanoparticles(semi-solids), crystalline or amorphous materials, complex particleswith ingredients embedded in a solid, semi-solid or liquid matrix,complex particles with ingredients encapsulated by solid, semi-solid orliquid materials, polymer particles, and high purity chemicals (notnecessarily containing particles), to name a few. Such materials aregenerally produced by creating two liquid phases and mixing the phasestogether. In some embodiments, the phases are miscible. In someembodiments, the phases are immiscible. In embodiments including mostlyhydrophobic or mostly hydrophilic constituents, the phases are referredto as the “oil phase” and the “water phase.”

In some embodiments, the oil phase may contain an oil phase constituentselected from vegetable oil (including, without limitation, soybean oil,olive oil, palm oil, corn oil, canola oil, sesame oil, rice oil, refinedvegetable oils, oils rich in omega-3 fatty acids, and algal oil), nutoils, animal oils (including, without limitation, fish oil), inorganicoils (including, without limitation, mineral oil, perfluorocarbon oilsincluding, without limitation, FC43, and perfluorodecalin), lipids(including, without limitation, egg phospholipids, lecithin,phosphatidylcholine, cholesterol, Palmitoyl oleoyl phosphatidylcholine,cationic lipids, and anionic lipids), modified or functionalized lipids(Hydrogenated phosphatidyl choline from soybean lecithin,N-(Methylpolyoxyethyleneoxycarbonyl)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and sodiumsalt (DSPE-PEG), waxes (including, without limitation, beeswax, andparaffin wax), surfactants (including, without limitation, Tween®,Span®, poloxamers such as 188, Solutol® such as polyethylene glycol(15)-hydroxystearate, block co-polymers), polymers (including, withoutlimitation, poly lactic acid (PLA), poly lactide-co-glycolide (PLGA),poly-epsilon-caprolactone, poly styrene, acrylics such as poly methylmethacrylate, crosslinked polymers, alginates, and mixtures ofpolymers), active ingredients (including, without limitation,pharmaceutical, nutraceutical, cosmeceutical, small molecules, proteins,peptides, RNA and DNA, anti-oxidants such as vitamin E and K, cannabisproducts (CBD/THC), cancer therapeutics, anesthetics, ocular drugs,antibiotics, and inhalable drugs), flavorings and colorings (natural orsynthetic flavoring oils), alcohols (including, without limitation,ethanol, methanol, benzyl alcohol, ethylene glycol, and propanol),organic solvents (including, without limitation, acetone, DMSO,alcohols, ethyl acetate, ethylene chloride, hexane, toluene, andpolyethylene glycols of various molecular weights), and/or derivativesof any of the foregoing constituents including, without limitation,fluorinated, pegylated brominated, and hydrogenated.

In some embodiments, the water phase may contain a water phaseconstituent selected from water, lipids (including, without limitation,egg phospholipids, lecithin, phosphatidylcholine, cholesterol, Palmitoyloleoyl phosphatidylcholine, sterols, neutral lipids, cationic lipids,and anionic lipids), modified or functionalized lipids (including,without limitation, hydrogenated phosphatidyl choline from soybeanlecithin, N-(Methylpolyoxyethyleneoxycarbonyl)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and sodiumsalt (DSPE-PEG)), surfactants (including, without limitation, Tween®,Span®, poloxamers such as 188 and 407, Solutol® such as Polyethyleneglycol (15)-hydroxystearate, block co-polymers, polysaccharides, casein,lecithin, whey protein, gelatin, mono- and di-glycerides, derivativessuch as acetylated, succinylated and diacetylated tartaric esters ofdistilled monoglycerides, lactylated esters, sorbitan esters,polysorbates, propylene glycol esters, sucrose esters, and polyglycerolesters), viscosity modifiers (including, without limitation, glycerol),pH adjusters (including, without limitation, sodium hydroxide, sodiumphosphate, potassium phosphate, sodium oleate, citric acid, hydrochloricacid, nitric acid, acetic acid, and buffers), and sugars (including,without limitation, sucrose, fructose, polysaccharides, and starches).

Each of the disclosed system designs may be advantageously employedaccording to the present disclosure to achieve variable/desired ratiosbetween feed streams within the downstream microreactor.

B. Exemplary Process Implementations

The disclosed apparatus/system may be used in a wide range ofapplications and/or implementations, e.g., particle size reductionapplications (e.g., emulsion and suspension applications), celldisruption application (e.g., E. coli and yeast applications), andreaction applications (e.g., crystallization applications). Severalexemplary applications/implementations are described herein below.However, such exemplary applications/implementations are merelyillustrative, and are not limiting with respect to the scope of thepresent disclosure.

Before describing specific exemplary implementations of the presentdisclosure by way of “examples” herein below, several broad principleshaving applicability to the disclosed apparatus/systems and theirapplication are described. These broad principles may be employed toidentify, evaluate, implement and/or enhance operations according to thepresent disclosure.

(1) Physical Processes

Examples of physical processes that may be facilitated and/or supportedaccording to the present disclosure include crystallization processes,precipitation processes, emulsion formation processes, particle coatingprocesses, and particle mixing processes. The foregoing processesgenerally benefit from molecular interaction at the nanometer scale.Each of these processes can be undertaken using the disclosedapparatus/systems according to different methods and/or roadmaps (i.e.,processing of specific constituents under specific process parameters toachieve specific results), as will be readily apparent to personsskilled in the art. For example, processing a solvent and antisolventstream (and optionally a surfactant) with the disclosed apparatus/systemmay lead to crystallization or precipitation of the solute dissolved inthe solvent stream. Similarly, changing the pH of a solution by mixingthe initial solution with a stream that changes the pH of the finalsolution may result in crystallization and/or precipitation of thesolute.

In addition, emulsions may be formed by direct and continuousinteraction of continuous and dispersed phases, e.g., an oil stream withan aqueous/water stream. Typically, stable emulsions and nano-emulsionsare formed in two steps. Initially, a coarse pre-emulsion is made bymixing the immiscible liquids with conventional mixing equipment, suchas a propeller or a rotor/stator mixer. Subsequently, in someembodiments, the coarse emulsion may be processed using a standardMICROFLUIDIZER® processor (Microfluidics Corp., Newton, Mass.) or a highshear homogenizer. However, with the disclosed apparatus/system, thestep of producing pre-emulsions may be advantageously avoided.

Further, coating of solid particles can be achieved according to thepresent disclosure by interacting liquid suspensions of solid particleswith a solution containing the desired coating material(s). Coatings canthus be formed by physical or chemical adsorption of the coatingmaterial onto the particle surface.

(2) Chemical Processes (Chemical Reactions)

Chemical reactions of single or multiphase liquids can be enabled and/orexpedited according to the present disclosure, e.g., when reactantstreams are forced to interact inside the fixed, small volume geometryof a reaction chamber/microreactor. Flow through the reactionchamber/microreactor advantageously increases the interaction surfacearea among the reactant streams to a significant degree, therebyminimizing potential diffusion limitations and increasing reactionrates. Undesirable side reactions and/or slow reactions can be minimizedby creating conditions within the disclosed reactionchamber/microreactor, wherein the conditions are analogous to a “wellstirred reactor”. Indeed, the disclosed apparatus/systems may beeffective in avoiding reactions that are a result of concentrationgradients.

Exemplary chemical reaction categories that are supported by thedisclosed apparatus/systems include, without limitation, acid-basereactions, ion exchange processes, reduction/oxidation reactions,polymerization reactions, precipitation reactions, substitutionreactions, crosslinking reactions, reactive crystallization reactions,biodiesel reactions, and the like. More particularly, the followingexemplary application/implementation categories may benefit fromprocessing with the disclosed apparatus/system: (i) production ofnanoparticles via crystallization, precipitation or chemical reactions;(ii) coating of particles; (iii) mixing of heterogeneous materials atthe nanometer scale; (iv) expediting chemical reactions, and (v) ProcessIntensification

C. Performance Enhancement

According to testing performed according to the present disclosure,mixing intensity may be identified from estimates of the length scalesassociated with turbulent eddies (and thus Kolmogorov diffusion lengths)in the nanometer range. Time scales for the macro-, meso-, andmicro-mixing processes may thus be estimated and, along with the lengthscales, prediction of operational roadmaps may be undertaken thatcorrelate well with transport rates, particle size observations, andwell established theoretical approaches. Such testing permitsenhancement of system performance, such that the disclosed apparatus,systems and methods may be effectively and advantageously used, interalia, to measure millisecond kinetics, conduct micro-scale reactions,facilitate formation of nano-emulsions/suspensions via turbulent mixing,and achieve enhanced mass transfer operations needed for controllednucleation and growth in precipitation and crystallization, e.g., forprotein and inorganic substances.

Representative values for system parameters according to exemplaryimplementations and/or applications of the present disclosure are asfollows:

-   -   reaction chamber residence times from 0.5-1 ms;    -   micro-mixing time scales of 1-4 μs;    -   turbulent energy dissipation rates on the order 107-108 W/kg;    -   nano-emulsion droplet and particle diameters in the range 25-500        nm:    -   diffusion coefficients from 1-5×10−9 m2/s; and    -   interface transfer coefficients as high as 0.5 m/s.    -   Chemical conversion and pathway selectivity of 100% can be        advantageously demonstrated according to exemplary        implementations of the present disclosure.

As a general principle, process intensification (PI) facilitatesintegration of operational steps within a smaller number ofscale-reduction vessels, thereby supporting miniaturization of unitoperations and processes. In situ separation schemes within continuousflow micro-reactors are classic examples. Adaptation of PI strategiesbased on the present disclosure provides numerous benefits. Exemplaryadvantageous outcomes that may be realized through adaptation of thedisclosed PI strategies include:

-   -   High throughput with higher product purity and uniformity;    -   Efficient start-up and shut-down procedures, which translates        to, inter alia, reduced inventory/surge systems and reduced        “off-specification” material;    -   Decreased expenditures, which translates to, inter alia,        low/reduced capital costs, lower energy use and reductions in        other operating costs, and reduced space requirements/smaller        plant footprint;    -   Enhanced operability and control;    -   Environmental advantages and/or pollution prevention;    -   Lower plant profile; and    -   Safety benefits, which translate to, inter alia, decreased        volumes of explosive, hazardous or toxic compounds, enhanced        operator friendliness, and potential isolation in secondary        containment chambers, as desired.

The apparatus/systems and methods of the present disclosure facilitateimproved reactor performance. In particular, the disclosed reactors canprovide a number of key advantages by, for example, cutting residencetimes, accelerating reaction rate, minimizing side reactions and/orreducing energy intensive downstream processing steps, such asdistillation and extraction. With many reactions, there are significantheat and mass transfer limitations which are determined by thecontacting patterns obtained via the intensity of mixing (i.e., thehydrodynamics). These heat/mass transfer limitations can thus controlthe observed system dynamics, rather than fundamental kinetics of thereaction system.

Depending on reaction dynamics of a particular system, there are severalways that apparent reaction rate of a particular system can be increasedaccording to the present disclosure. For example, mass transferlimitations that are common to heterogeneous reactions may be removed byincreasing the surface area-to-volume ratio of the dispersed phase. Oncethe mass transfer limitations are removed (or substantially reduced),the reaction may advantageously proceed according to the intrinsickinetics.

As a further example, enhanced identification and/or control of thetemperature profile throughout the reactor may be achieved, whichgenerally leads to better control of the reaction rate. By way ofillustration, a highly exothermic reaction carried out in a large batchvessel may require several hours, not because of any inherent kineticsconstraint but because of the time necessary to remove the heat ofreaction safely via its poor transfer area-to-volume ratio using atraditional coil configuration. With intense mixing and improved heattransfer mechanisms associated with the low holdup of material in thereactor, better productivity is possible according to the presentdisclosure. As a result of these enhanced transportcapabilities/features, the selectivity of a multiple reaction schemeincreases, resulting in improved product yields and quality with reducedseparation requirements.

Process data, connected with computational fluid dynamics (CFD)modeling, may advantageously provide a basis for design, redesign and/orreconfiguration of system designs and layouts. CFD can also be used topredict: (1) velocity and stress distribution maps in complex reactorperformance studies; (2) transport properties for non-ideal interfaces;and (3) materials processing capabilities useful in encapsulationtechnology and designing functional surfaces, especially whereself-assembly mechanisms, surface tension and interfacial forces, andturbulent energy driven processes dominate.

D. Precipitation and Crystallization Processes

Both precipitation and crystallization processes are characterized by asolid material that is formed from solution. Such processing schemes arewidely used in production of pharmaceutically active ingredients,proteins and other chemical products. The main difference in these twoprocesses is that precipitation produces a solid of poorly definedmorphology, whereas crystals grow with a well-defined 3-dimensionallattice structure. Typically, the primary objectives for bothprecipitation and crystallization processes are to (1) increaseconcentration, e.g., when precipitating from a dilute solution, and/or(2) purify a material, such as when selectively crystallizing onespecies from a solution containing multiple types.

Each process is generally initiated by changes in the thermodynamicstate of the solution, thereby reducing the solubility of the targetspecies. Initiation may thus be undertaken via temperatureadjustment(s), concentration adjustment(s), e.g., by addition ofantisolvents, or adjustment of solution activity coefficients, e.g., byaddition of ionic species. As an example, when dealing with solubilityof proteins, processing approaches may include: (1) pH adjustment to theisoelectric point, (2) addition of organic solvents, (3) increasingionic strength to cause salting out, and/or (4) addition of non-ionicpolymers.

Nucleation sites must be created to initiate precipitation and/orcrystallization processes, either by generating a very highsuper-saturation resulting in spontaneous growth (homogeneousnucleation) or seeding the solution with surfaces for growth(heterogeneous nucleation), whether inert or the desired target species.In all cases, it is essential that the solubility of the target speciesbe reduced below the actual concentration in solution. This effectivelycreates a concentration in excess of the thermodynamic equilibriumsaturation value and rate processes then dominate system behavior. Themagnitude of the difference from equilibrium, i.e., degree ofsuper-saturation, influences both type and rate of system response.

Precipitation conditions are often obtained via chemical reactionsproducing species with limited solubility in the reaction mixture. Thisis one method of generating the local high degrees of super-saturationrequired for desired rapid kinetics. The process occurs in four serial,but often overlapping, steps:

(1) The feed solution and reagent are mixed. The time required toachieve homogeneity is generally dependent on diffusivity of the targetspecies and distance the target species molecules must travel within themixing eddies (i.e., Kolmogorov length), which can be estimated usingturbulence theory. Calculation/analysis requires knowledge of the mixingpower input and subsequent energy dissipation rate per unit volume alongwith solution properties such as density and viscosity.

(2) Subsequent to the mixing step which is aimed at obtaining a desireddegree of super-saturation, nucleation of small solid particles occurs.The nucleation rate increases exponentially with respect tosuper-saturation up to a characteristic limiting rate, and the featuresof the product formed depend significantly on this rate. If thenucleation rate is too high, the result is likely to be a colloid (i.e.,highly solvated) and, thus, complicated downstream processing may berequired.

(3) Growth rate is determined by diffusion of solute molecules from thebulk solution to the solid surface and/or a surface integration rate,until a limiting particle size is reached. The limiting particle size isgenerally determined by the magnitude of shear in the mixed solution.

(4) Once the limiting particle size is reached, further growth is byflocculation, whereby particles collide and adhere to each other.Particle number thus decreases with time exponentially as the particlesize increases. Finally, as the particles grow in size, the shear forcesin the mixed solution cause fracture; resulting in a size plateau atlong mixing times.

Thus, important parameters in a precipitation process are (a) degree ofsuper-saturation achieved in the initial mixing, which is dependent uponreagent volume, and (b) shear stress in the mixed solution, which isproportional to power input per unit volume of solution.

Like precipitation, the crystallization process begins by reducing thesolubility of the target species. However, relatively low degrees ofsuper-saturation are utilized since, at high levels, the solids formedtend to be an amorphous precipitate (rather than crystalline). Controlof the rate processes, as discussed above, is essential to directing thepath to a desired final thermodynamic state and to achieving a desiredmorphology. Spontaneous formation of solids can entrap undesired speciesinto the lattice framework. Thus, slowing the growth rate byreducing/lowering the super-saturation level permits higher selectivityin the surface integration mechanism, i.e., crystals are formed that arevery pure due to exclusion of other contaminate species. Locally highshear forces can also help maintain appropriate/desirable transportgradients. Crystallization may thus be used as a primary separationmethod and/or as a finishing step to yield product of desired purityaccording to the present disclosure.

E. Nano-Encapsulation

The ability to form nanoscale particles and/or emulsions thatencapsulate active ingredients has applicability in many facets of theengineering biosciences. For example, nano-technologies are having amajor impact on drug delivery, molecular targeting, medical imaging andbiosensor development, as well as on cosmetic and personal careproducts, and nutraceutics. Unfortunately, conventional mixing equipmentin which a high shear, elongated flow field is generated near the tip ofhigh-speed blade(s) only generate emulsions with droplet sizes in therange 500 nm and larger. Such emulsions are stable only if sufficientsurface active agents are present to control agglomeration andre-growth. This approach to emulsion stability requires properdistribution of the surfactant for the appropriate surface coverage ofthe droplets, thereby minimizing Oswalt ripening and subsequentundesired size distribution changes. The higher shear rates achievedaccording to the present disclosure advantageously facilitate generationof stable mean particle sizes in the range 50 to 100 nm andrequisite/desired narrow particle size distributions. The disclosedsystems/techniques may also advantageously dispense with the need forsurfactants for stability, dependent upon the surface characteristics ofthe emulsion constituents and their intended applications.

F. Creating Nano-Scale Particles/Entities

High shear fields have been developed in the reactionchambers/microreactors of the present disclosure to produce particleswith diameters in the range 50 to 100 nm. Such particles are about thesize of the smallest turbulent eddies generated in such processingunits. For example, jet impingement on a solid surface (e.g. Z-typemicroreactor) or with another jet (e.g., Y-type microreactor) has beenshown to be highly efficient. Systems that incorporate high velocitylinear fluid jets that collide can rapidly reduce the scale ofsegregation between the streams. These jets can be considered as free,submerged, or confined. A free jet stream is not affected by the wallsof a surrounding chamber/vessel nor any surrounding fluid, in contrastto submerged jets where viscous drag forces may be significant. Withconfined impinging jets, the dimensions of the chamber/vessel relativeto jet diameter can play a major role in system performance.

The importance of chamber/vessel dimensions relative to jet diameter isapparent from the micro-mixing time and its relative magnitude comparedto the process characteristic time in such jet-based systems. Tominimize process sensitivity to mixing, it is generally necessary toreduce the mixing time constant (including macro-, meso-, andmicro-mixing) to a fraction of the most significant/relevant processtime constant. Length scales are typically used to classify mixingprocesses, i.e., macro-mixing occurs at vessel dimension scale,meso-mixing is at the turbulent eddy scale, and micro-mixing is on thescale of molecular diffusion in stretching fluid lamellae.

According to apparatus/systems of the present disclosure, high-energydissipation is observed in the disclosed microreactor designs becausethe kinetic energy of each stream is converted into a turbulent likemotion as the result of the collision and redirection of the flow, e.g.,within the very small volume defined by the reactionchamber/microreactor, and the associated shear forces. The size ofvirtual cylindrical volume elements of exemplary microreactors of thepresent disclosure may be quantified using computational fluid dynamics(CFD) techniques and has been calculated to be on the order of seven (7)to ten (10) jet diameters for the radial dimension of the impingementplane. The other cylinder dimension (height) has been shown to beindependent of jet diameter and the design thereof is typically relatedto the inter-penetration length of the two jets. In exemplaryembodiments of the present disclosure, the height dimension iscalculated to be about 10 percent of the inter-nozzle (jet separation)distance.

Interfacial mass transfer area may be used to characterize mixingquality and to quantify associated length scales. Using known transferareas, diffusion lengths, and physico-chemical properties of fluids thatpermit measurement of appropriate rate phenomena to determine transportparameters, it is possible to determine an interfacial transfercoefficient, mass diffusivity, and a system characteristic timeconstant. Connecting these fundamental parameters with system geometricconfigurations, operating variables and measured performance metrics(such as quantity transported and approach to equilibrium, if notobtained), it is possible to determine transfer areas that mustnecessarily be present in an reaction chamber/microreactor. In addition,from this interfacial area, it is possible to identify the eddy sizescale (i.e., Kolmogorov diffusion length). Consequently, a measure ofmixing intensity can be obtained which provides a basis for predictingand/or achieving desired average droplet sizes when generatingnano-emulsions and other dispersed systems.

G. Flow Patterns, Mixing and Transport Phenomena

As is readily apparent, it is important to design systems withappropriate hydrodynamic characteristics with respect to transportphenomena and effects on dynamic response (whether chemical reactionkinetics or other rate processes). Beyond system design, processinnovations are disclosed herein that (i) utilize flow instabilities formixing, (ii) improve contacting patterns to enhance interactions thatpromote better kinetics performance and transport rates, and (iii)improve transport via mechanical turbulence promoters.

Description of Process and Controls for a Method for ContinuouslyProcessing at Least Two Liquid Feed Streams

A. Process

The process has the following steps:

1. Determining the Volume Factions of Each of the Liquid Streams

This step generally starts with the desired formulation of the finalproduct at each stage of processing. The examples below show how to setup the system of the present disclosure to create an emulsion from twoimmiscible liquid streams. This similar procedure is used when mixingmiscible liquid streams for the purpose of conducting crystallization,precipitation, and chemical reactions, among others.

Option 1. In this option, an oil/water emulsion in which the oil phaseis 5% by volume and the water phase is 95% by volume is created. Thevolume fraction of the oil phase of the emulsion in the finalformulation is 5/100=0.05 while the fraction of the water phase is95/100=0.95. The ratio of the two streams, water to oil, is0.95/0.05=19. During processing, this ratio must stay constant at thisratio value or deviate little from this ratio value to achieve a finalformulation with the desired composition.

Option 2. The desired formulation of the final product may be differentthan the formulation at intermediate stages. In Option 1, it is possiblethat the oil phase is delivered in two steps. For example, in the firststep, half of the oil is delivered to the water phase to create anemulsion with 2.5% by volume oil. In the second step, this firstemulsion becomes one of the streams, while the other stream consists theremainder of the oil. The ratio of the water to the oil in the firstemulsion is 0.975/0.025=39. The volume ratio of the first emulsion tothe second (and final) oil stream is 100/0.025=40.

Option 3. It is possible that a concentrated emulsion is homogenized.After homogenization, the concentrated emulsion may be diluted furtherwith addition of the continuous (water) phase or parts of the waterphase. In Option 2, it may be possible to homogenize an emulsioncontaining 10 vol % oil without sacrificing the particle size. Thisemulsion is then diluted with the addition of the water phase or purewater such that the final concentration of the oil phase in the emulsionis 5 vol %.

B. Flowrate Calibration

The flow rate of each stream is calculated as follows.

The total flow rate of the system of the present disclosure is measuredat the outlet of the homogenizer. Subsequently, each of the meteringpumps is set to provide the appropriate flow rate based on the desiredvolume fraction of the particular stream in the final formulation. Thetotal flow rate of the homogenizer is measured under set conditions ofpressure, hardware, type of in-line mixer upstream, and temperature whena single stream of the material is processed. The flow rate of each ofthe streams is calculated by multiplying the total flow rate with thepercentage of that stream in the formulation, the final or intermediate,based on the specific formulation.

In Option 1 of the previous section, to produce a 5% by volumeoil-in-water emulsion when the total flow rate is 300 ml/min, the oilmetering pump (if present) should be set at 15 ml/min (5% of 300 ml/min)while the water metering pump (if present) should be set at 285 ml/min(85% of 300 ml/min). The flow rate of the input streams not having adedicated metering pump may be controlled indirectly by the pumpingaction of the homogenizer.

There may be hardware configurations that have a metering pump for eachinput liquid stream. Such configurations are in addition to an optionalmain pump that feeds the homogenizer, which is located downstream of themetering pump, as shown in FIG. 1.

Finally, there may be hardware configurations which do not have a mainfeed pump for the homogenizer because the homogenizer is self-fed. Theflows in this configuration can be calibrated as described above.

The accuracy of the calibration may be optionally verified by conductinganalytical testing on the final formulation to verify that the finalcomposition is within the acceptable range.

2. Homogenization

2.1 Priming

Priming is completed to remove air from the system of the presentdisclosure, which, in some embodiments, includes the metering pump(s),the in-line mixer, the feed pump(s), the homogenizer, and the linesconnecting those. Priming is accomplished by passing a liquid throughthe system generally at a low pressure. Optionally, priming is sometimescompleted using the stream with the highest flow rate or the stream withconstituents that are readily available or inexpensive.

2.2 Processing

Once the homogenizer is primed, the pressure is set to the desired valueand the pump of the second stream is turned on. The initial volume equalto the holdup volume of the machine is discarded because it does notcontain ingredients from the second stream.

Once the homogenizer is set at the correct pressure and the initialmaterial is discarded, the homogenizer produces the material with thedesired composition. Following the first pass of the liquid streamsthrough the homogenizer, there may be several other processes dependingon the outcome of the first pass.

It is possible that the first pass through the homogenizer does notresult in the desired product quality in terms of particle size orcomposition. In this case, further processing steps may be required asfollows:

(a) If the composition of the formulation is similar to the desiredformulation but the particle size is larger than desired, the materialis processed through the homogenizer a few more times, if necessary,until the desired particle size is achieved. In this case, after thefirst pass, a single liquid stream will be processed each time throughthe homogenizer.

(b) If the composition of the formulation is incorrect because, forexample, only part of the one liquid stream had been incorporated in thepreliminary formulation, the remaining material may be incorporated in asimilar method during a second pass through the homogenizer. In thiscase, for example, the end formulation from the first pass mayconstitute one of the streams in the second pass.

(c) A combination of (a) and (b) may be required in some embodiments.

3. Dilution

If the final concentration is higher than that desired, dilution may beappropriate.

4. Quenching

Quenching is used to stop processes from continuing. For example,quenching may be used to stop a chemical reaction and/or crystal growthduring crystallization, to prevent oil droplets from coalescing witheach other, and/or to prevent particles from agglomerating, amongothers.

5. Aseptic filtration

6. Lyophilization

C. Controls

1. Flowrate Ratio Control

It is possible to control the flow rate ratio in real time or at acertain frequency during operation. This is conducted by first measuringeither directly or indirectly the total flow rate of the system at theend of the homogenizer at a certain frequency, and then adjusting theflow rate of each stream based on the desired flow rate ratio of eachstream.

Referring now to FIG. 8, an illustrative system 800 for continuouslyprocessing at least two liquid feed streams in accordance with thepresent disclosure is schematically depicted. A flowmeter 802 ispositioned on conduit 126 in between heat exchange unit 124 andcollection tank 128. Flowmeter 802 measures the total flow rate of thesystem 800. Direct measurements of the flow rate ratio may be conductedwith the use of flowmeter 802. In some embodiments, gravimetricmeasurements may be performed. Indirect measurements may be conducted bycounting the stroke rate of the microreactor 120. In embodiments inwhich the microreactor 120 is a constant pressure homogenizer, suchhomogenizers typically deliver a constant liquid volume per stroke. Insome embodiments, an electronic signal, which is related to themagnitude of the flow rate (input signal), may be generated. Based onthe input signal, output electronic signal(s) 804 may be generated byflowmeter 802 and delivered to pump 106. In some embodiments, outputelectronic signal(s) 804 are delivered to pump 106 via electrical wiring(not shown) or wirelessly (not shown). Output electronic signal(s) 804may be estimated to represent the desired flow rate of each stream.Output electronic signal(s) 804 are used to control the flow rate ofpump 106. In some embodiments, the output electronic signal(s) 804control of pump 106 occurs in real time. In some embodiments (notshown), output electronic signal(s) 804 are used to control the flowrate of valves (not shown).

2. Emergency Stop

Referring now to FIG. 9, an illustrative system 900 for continuouslyprocessing at least two liquid feed streams in accordance with thepresent disclosure is schematically depicted. Emergency Stop (E-Stop)902 is electrically connected to microreactor 120 and pump 106. In someembodiments, E-Stop 902 is electrically connected to microreactor 120and pump 106 via electrical wiring or wirelessly. E-Stop 902 iselectrically connected to a switch 904. Pump 106 and microreactor 120are electronically connected to E-Stop 902. In some embodiments, E-Stop902 is connected to any suitable equipment used in system 900.

The E-Stop 902 is utilized to stop all key equipment in system 900 atthe same time in case of an emergency. If the microreactor 120 stopswhile the pump 106 is operating, it is possible that the feed lines areover pressurized or expensive material may be leaking or otherwisewasted. The E-Stop 902 is designed such that when the microreactor 902stops, the E-Stop 902 forces the pump 106 to stop. Additionally, if themicroreactor 120 is slowing down or speeding up due to blockage or lossof liquid streams, respectively, the pump 106 is forced to stop.

In some embodiments, a single E-Stop 902 is utilized for the pump 106,the microreactor 120, automated valves (not shown), and other upstreamand downstream pieces of equipment (not shown). Switch 904 is utilizedin system 900 to turn off the power to any equipment that is connectedto the E-Stop 902.

EXAMPLES

The following non-limiting examples illustrate certain advantages andimprovements of the apparatus/systems and methods for continuouslyprocessing at least two liquid feed streams according to someembodiments of the present disclosure. These examples are meant to beillustrative only and are not intended to limit or preclude otherembodiments of the present disclosure.

Example 1 Oil/Water Emulsion Using the Dual Feed Emulsification Method

The formulation by weight and by volume shown in Table 1 is prepared.

TABLE 1 Batch Size 100 g 100 ml (g) (ml) Mineral oil 37.00 44.58 Tween80 2.40 Water 60.60 55.42

The water (60.60 g) is heated in a beaker on a hot plate to 55° C.Tween® 80 (2.40 g) is added to the water while the mixture is stirredconstantly with a magnetic stirrer until the Tween® 80 is completelydissolved. The mineral oil is also heated to 55° C.

After 1-2 minutes, the oil is poured into the water while the mixture ishomogenized using a rotor-stator mixer (T25 Ultra Turrax, IKA) that isrotating at 20,000 rpm. After a total mixing time of 5 minutes, a coarseemulsion is poured into the reservoir of a HP350-30 high-pressurehomogenizer available from DyHydromatics, LLC (Maynard, Mass. USA). Asmall amount of the coarse emulsion is saved for further analysis.

The high pressure homogenizer is set to 20,000 psi and is equipped withtwo reaction chambers in series, suitable for emulsions. The reactionchambers are the 75.3T and the 200.2L, respectively, which are availablefrom DyHydromatics, LLC. Downstream of the reaction chambers is a coilheat exchanger, which cools the processed material using water at 21° C.as a cooler. The equipment is preheated with hot water to 55-60° C.prior to processing the emulsion. The emulsion is passed three timesthrough the homogenizer at initial temperatures 55, 37, and 30° C. ateach pass, respectively. The emulsion is then collected and the particlesize analysis is performed.

Particle size analysis is performed using a PSA 1190 L/D LaserDiffraction instrument available from Anton Paar and a Litesizer™ 500Dynamic Light Scattering instrument also from Anton Paar. The resultsare shown below.

Coarse Emulsion:

-   -   Median Particle size (vol.): 8.44 microns

Final Emulsion:

-   -   Hydrodynamic Diameter: 280 nm    -   Polydispersivity Index: 17.4%

Example 2 Oil/Water Emulsion Using the Method of the Present Disclosure

The formulation by weight and by volume shown in Table 2 is prepared.

TABLE 2 Batch Size 100 g 100 ml (g) (ml) Mineral oil 37,00 44.58 Tween80 2.40 Water 60,60 55.42

The water (60.60 g) is heated in a beaker on a hot plate to 55° C.Tween® 80 (2.40 g) is added to the water while the mixture is stirredconstantly with a magnetic stirrer until the Tween® 80 is completelydissolved. The mineral oil is also heated to 55° C.

A high pressure homogenizer, HP350-30 from DyHydromatics, LLC (Maynard,Mass. USA) is fitted with Delphi Scientific, LLC's dual feed DF-X-01. A6 inch in-line, static mixer (¼-40-3-12-2) is obtained from KofloCorporation (Cary, Ill.). A peristaltic pump, Model BT101L-CE VersionV122S121 with #15 tubing from Golander, LLC (Norcross, Ga.), is used topump the oil to the homogenizer at a predetermined rate.

The high pressure homogenizer is set to 20,000 psi and is equipped withtwo reaction chambers in series, suitable for emulsions. The reactionchambers are the 75.3T and the 200.2L, respectively, which are availablefrom DyHydromatics, LLC. Downstream of the reaction chambers is a coilheat exchanger, which cools the processed material using water at 21° C.as a cooler. The homogenizer, dual feed, and all lines are preheatedwith hot water to 55-60° C. prior to processing.

The flow rate of the homogenizer is first determined under theseprocessing conditions, and such flow rate is measured to be 403 ml/min.Subsequently, the density of the oil is measured at 55° C., and suchdensity is found to be 0.83 g/ml. Therefore, the volume fraction of theoil phase is calculated and shown on Table 2. The flow rate of the oilis then estimated to be 403*44.58/100=179.65 ml/min. The peristalticpump is set to 179.65 ml/min.

The initial temperatures at each pass through the homogenizer are 55,37, and 30° C. at each pass, respectively. The emulsion is thencollected and the particle size analysis is performed.

Particle size analysis is performed using a PSA 1190 L/D LaserDiffraction instrument available from Anton Paar and a Litesizer™ 500Dynamic Light Scattering instrument also available from Anton Paar. Theresults are shown below.

Final Emulsion:

-   -   Hydrodynamic Diameter: 241 nm    -   Polydispersivity Index: 9.6%

Compared to the emulsion of EXAMPLE 1 prepared with the conventionalDual Feed Emulsification Method, the emulsion of EXAMPLE 2 preparedusing the method of the present disclosure has smaller particle size(241 nm versus 280 nm), and narrower particle size distribution asinferred by the low Polydispersivity Index (9.6% versus 17.4%).

Examples 3 and 4 compare two different feed systems in terms of accuracyin achieving the desired ratio of the two streams and, therefore, thedesired formulation.

Example 3

Propofol emulsion is an emulsion used in anesthesia worldwide. A commonformulation of the propofol emulsion shown in Table 3 is prepared.

TABLE 3 Batch size 100 g 100 ml (g) (ml) Oil Phase Propofol 1 Soybeanoil 5 Medium chain triglycerides 5 TOTAL OIL PHASE 11 11.84 Water PhaseEgg Lecithin 1.2 Glycerol 2.25 Sodium Oleate 0.04 WFI 85.51 TOTAL WATERPHASE 89 88.16 TOTAL FORMULATION 100 100

A 400 g batch of propofol emulsion is prepared based on the formulationshown in Table 3 (second column). Water for Injection (WFI) is heated ina beaker on a hot plate to 45° C. Egg lecithin, glycerol, and sodiumoleate are added, and the mixture is stirred until all ingredients aredissolved. All ingredients of the oil phase are placed in a beaker andheated to 45° C. The density of the oil and water phases are measured bymeasuring the weight of a certain volume of each phase. Based on theseresults, the oil phase is found to be 11.84 vol % and the water phase isfound to be 88.16 wt %.

A high pressure homogenizer, HP350-30 from DyHydromatics, LLC (Maynard,Mass. USA) is fitted with Delphi Scientific LLC's dual feed DF-X-01. A 6inch in-line, static mixer (¼-40-3-12-2) is obtained from KofloCorporation (Cary, Ill.). A peristaltic pump, Model BT101L-CE VersionV122S121 with #15 tubing from Golander, LLC (Norcross, Ga.), is used topump the oil to the homogenizer at a predetermined rate.

The oil and water phases are then fed separately to a high pressurehomogenizer, HP350-30 from DyHydromatics, LLC (Maynard, Mass. USA). Thehigh pressure homogenizer is set to 21,000 psi and is equipped with tworeaction chambers in series, suitable for emulsions. The reactionchambers are the 75.3T and the 200.2L, respectively, which are availablefrom DyHydromatics, LLC. Downstream of the reaction chambers is a coilheat exchanger, which cools the processed material using water at 21° C.as a cooler. The homogenizer, dual feed, and all lines are preheatedwith hot water to 45-50° C. prior to processing.

The flow rate of the homogenizer is first determined under theseprocessing conditions, and such flow rate is measured to be 367 ml/min.The flow rate of the oil is then estimated to be 367*11.84/100=40.65ml/min. The peristaltic pump that feeds the oil phase is set to 43.45ml/min.

Initially the homogenizer, the inline mixer, and all lines are primedwith water to displace the air. Subsequently, the water phase is pouredinto the reservoir of the homogenizer, while the oil phase is pouredinto a beaker. The inlet tubing of the peristaltic pump is dipped insidethe oil phase and the outlet is connected to one of the ports of theinline mixer. The homogenizer and the peristaltic pump are started. Theprocessed emulsion is collected from the outlet of the homogenizer.

This process is continued until all water and almost all oil isconsumed. The amount of the emulsion that is collected and the remainingoil are weighted separately. Based on the amount of oil remaining, theconcentration of oil in the emulsion is calculated to be 11.16 wt %,which corresponds to 1.45% higher oil concentration (and therefore drugconcentration) of the formulation when compared to the desired 11 wt %oil. These results are within the acceptable range, which is usually+/−2% from an average value. Additionally, if desired the emulsion maybe slightly diluted to achieve the desired 11%.

Example 4

The formulation of Example 3 shown in Table 3 is used in Example 4.

A 400 g batch of the propofol emulsion is prepared based on theformulation shown in Table 3 (second column). Water For Injection (WFI)is heated up in a beaker on a hot plate to 45° C. Egg lecithin,glycerol, and sodium oleate are added and the mixture is stirred untilall ingredients are dissolved. All ingredients of the oil phase areplaced in a beaker and heated to 45° C. The density of the oil and waterphases are measured by measuring the weight of a certain volume of eachphase. Based on these results, the oil phase is found to be 11.84 vol %and the water phase 88.16 wt %.

A high pressure homogenizer, HP350-30 from DyHydromatics, LLC (Maynard,Mass. USA) is fitted with a feed system substantially similar to thatdescribed in U.S. Pat. Nos. 8,367,004 and 8,187,554, which are assignedto Microfluidics International Corporation, (co-axial feed). Aperistaltic pump, Model BT101L-CE Version V122S121 with #15 tubing fromGolander, LLC (Norcross, Ga.) is used to pump the water phase. Anotherperistaltic pump, from LongerPump (Tucson, Ariz.), model YZ1515x withtubing L/S 16 from Masterflex from Cole Palmer (Vernon Hills, Ill.), isused to pump the oil phase. The outlet of each pump is connected to oneof the two inlets of a co-axial feed, and such feed consists of twoconcentric tubes and is positioned at the inlet of the homogenizer. Eachliquid stream flows into one tube, and therefore there is no mixing ofthe two streams until such streams reach the inlet of the homogenizer.

The flow rate of the homogenizer is first determined under theseprocessing conditions, and such flow rate is measured to be 367 ml/min.Subsequently, the density of the oil is measured at 45° C., and suchdensity is found to be 0.92 g/ml. Therefore, the volume fraction of theoil phase is calculated and shown in Table 3. The flow rate of the oilis then estimated to be 367*11.84/100=43.45 ml/min. The peristaltic pumpthat feeds the oil phase is set to 43.45 ml/min, while the other pump isset to 367−43.45=323.55 ml/min.

Initially the homogenizer, the co-axial feed, and all lines are primedwith water to displace the air. Subsequently, the oil and water phasesare poured in two separate beakers. The inlet tubing of each peristalticpump is dipped inside one beaker and the outlet is connected to one ofthe ports of the co-axial feed. The homogenizer and the peristalticpumps are started. The processed emulsion is collected from the outletof the homogenizer.

It is noticed initially that a mostly water phase exited thehomogenizer, which is easy to determine because the water phase is lightyellow and fairly translucent while the processed emulsion is opaque andwhite in color. The water phase is discarded. Eventually, the whiteemulsion began to exit the homogenizer. The white emulsion is collectedin a beaker.

This process is continued until almost all oil and water phases areconsumed. The amount of the emulsion that is collected and the remainingoil and water phases are weighed separately. Based on the amount of oiland water phases remaining, the concentration of oil in the emulsion iscalculated to be 9.97 wt %, which corresponds to 9.34% error in oilconcentration (and therefore the drug concentration) of the formulationwhen compared to the desired 11 wt % oil. The formulation prepared inthis EXAMPLE 4 is outside of the acceptable range, and such formulationcannot be diluted further to achieve the acceptable specifications.

Example 5

The formulation Example 2 shown in Table 2 is used in the systemdescribed in EXAMPLE 4. The set point of the flow rate of the oil pumpis increased by 9.34% to 47.54 ml/min (by 4.09 ml/min) while the flowrate of the water is decreased by the same amount (4.09 ml/min), whichwould simulate automatic control of the pump flow rates.

After the experiment, the oil content is inferred, and such oil contentis found to be 9.97 wt %. The oil content is again lower than thedesirable by 9.36%, which is unacceptable in most applications.

Example 6

Norfloxacin (NFN), which is a highly hydrophobic (having limitedsolubility in water) pharmaceutical, is selected as a model drug todemonstrate the applicability of the disclosed apparatus, systems andmethods based on: (a) limited water solubility, (b) availability, and(c) price. Norfloxacin is recrystallized using the method of the presentdisclosure to obtain submicron particles. Such particles may increasethe bioavailability of norfloxacin, which such bioavailability islimited by norfloxacin's limited water solubility.

10 mg of norfloxacin is dissolved completely in 40 g of dimethylsulfoxide (DMSO) at about 30° C. and is mixed using a magnetic stirrer.About 160 ml of water is mixed with 2 grams of surfactant Tween® 80.When the stream of norvloxacin dissolved in DMSO mixes with the streamof water mixed with Tween® 80, the norfloxacin is not soluble in themixture of the DMSO, water, and Tween® 80. Therefore, the norfloxacincrystallizes.

The system described in Example 2 is used for processing. The total flowrate of the equipment is 403 ml/min. The density of the DMSO phase isdetermined to be 1.1 g/ml. The desired volume fraction of the DMSO phasecompared to the total volume flow rate of the machine is 18.48%. Thetotal flow rate of the peristaltic pump that delivers the DMSO phase isset to 74.48 ml/min.

The two streams are processed once through the equipment to ensuremixing and interaction of the full amount of the DMSO phase with thewater phase. A liquid dispersion containing white norfloxacin particlesis obtained, and such dispersion is then again passed through thehomogenizer. This time the port that delivered the DMSO mixture is notused and is closed. The dispersion is poured into the machine reservoirand is delivered to the homogenizer as a single mixture. The dispersionis processed again to de-agglomerate possible agglomerates formed duringthe first pass.

Particle size of the material is conducted using a Litesizer DynamicLight Scattering instrument available from Anton Paar. The averageparticle size is found to be 154 nm.

Although the present disclosure has been described with reference toexemplary embodiments and implementations thereof, the presentdisclosure is not limited by such illustrativeembodiments/implementations. Rather, the present disclosure is subjectto changes, modifications, enhancements and/or variations with departingfrom the spirit or scope hereof. Indeed, the present disclosureexpressly encompasses all such changes, modifications, enhancements andvariations within its scope.

1-58. (canceled)
 59. A method for continuously processing at least twoliquid feed streams, comprising: pumping a first feed stream to a mixer;flowing a second feed stream to the mixer without pumping the secondfeed stream to the mixture; mixing the first and second feed streams toachieve a substantially homogeneous mixture; and pumping thesubstantially homogeneous mixture to a high pressure pump, whereinmixing the first and second feed streams to achieve the substantiallyhomogenous mixture includes mixing the first and second feed streamswith the mixer at a location that is upstream of the high pressure pumpand upstream of a component arranged between the mixer and the highpressure pump, and wherein the component is selected from one of thefollowing: a conduit, a tank, a valve, a pump, a filter, a screen, asensor, or a port.
 60. The method of claim 59, further comprising:pressurizing the substantially homogeneous mixture within the highpressure pump to an elevated pressure; and delivering the substantiallyhomogeneous mixture to a microreactor downstream from the high pressurepump to cause the first and second feed streams to interact within themicroreactor at a nanoscale level.
 61. The method of claim 60, wherein:pressurizing the substantially homogeneous mixture within the highpressure pump includes pressurizing the substantially homogeneousmixture to an elevated pressure of at least 35 MPa; and delivering thesubstantially homogeneous mixture to the microreactor includesdelivering the substantially homogeneous mixture to a microreactorhaving a minimum channel dimension of equal to or less than 500 microns.62. The method of claim 60, wherein: the first feed stream includes afirst reactant; the second feed stream includes a second reactant; andthe method further comprises adjusting reaction selectivity bycontrolling interaction between the first and second reactants prior tonanoscale level interaction within the microreactor.
 63. The method ofclaim 60, wherein: the first feed stream includes a first reactant; thesecond feed stream includes a second reactant; and delivering thesubstantially homogeneous mixture to the microreactor downstream fromthe high pressure pump causes interaction to occur between the firstreactant and the second reactant according to at least one of thefollowing chemical processes: mixing, crystallization, precipitation,encapsulation, physical adsorption, chemisorption, substitutionreaction, oxidation reaction, reduction reaction, polymerizationreaction, acid-base reaction, and crosslinking reaction.
 64. The methodof claim 60, wherein: the first feed stream includes at least onereactant selected from a first group of reactants; the second feedstream includes at least one reactant selected from a second group ofreactants; delivering the substantially homogeneous mixture to themicroreactor downstream from the high pressure pump causes interactionto occur between the at least one reactant of the first group ofreactants and the at least one reactant of the second group of reactantsaccording to at least one of the following chemical processes: mixing,crystallization, precipitation, encapsulation, physical adsorption,chemisorption, substitution reaction, oxidation reaction, reductionreaction, polymerization reaction, acid-base reaction, and crosslinkingreaction; and the method further comprises (i) selecting, during eachiteration of performing the method, a reactant from the first group ofreactants that is different from the at least one reactant of the firstgroup of reactants and a reactant from the second group of reactantsthat is different from the at least one reactant of the second group ofreactants, and (ii) delivering the substantially homogeneous mixture tothe microreactor downstream from the high pressure pump to causeencapsulation to occur between the reactant from the first group ofreactants and the reactant from the second group of reactants such thatlayered particles are created with each layer having differentconsistencies or properties.
 65. The method of claim 60, wherein: thefirst feed stream includes a solvent; the second feed stream includes anantisolvent; interaction between the solvent and the antisolvent withinthe microreactor is effective to define a nanosuspension; and the methodfurther comprises obtaining constituent nanoparticle crystals oramorphous nanoparticles from the nanosuspension.
 66. The method of claim65, further comprising cooling or quenching the nanosuspension afterinteraction within the microreactor.
 67. The method of claim 59,wherein: pumping the first feed stream to the mixer includes pumping thefirst feed stream to the mixer at an actively, automatically controlledrate; and pumping the substantially homogeneous mixture to the highpressure pump includes pumping the substantially homogenous mixture tothe high pressure pump at a controlled or an actively controlled rate.68. The method of claim 67, wherein the actively controlled rate fordelivery of the first feed stream to the mixer is effected by anactively controlled feed pump for the first feed stream.
 69. A systemfor continuously processing at least two liquid feed streams,comprising: a feed pump adapted to pump a first feed stream downstream;a mixer positioned to receive the first feed stream from the feed pumpand a second feed stream from a feed line and adapted to mix the firstand second feed streams to achieve a substantially homogeneous mixture;and a high pressure pump positioned to receive the substantiallyhomogeneous mixture from the mixer, wherein the mixer is locatedupstream of the high pressure pump and upstream of a component arrangedbetween the mixer and the high pressure pump, and wherein the componentis selected from one of the following: a conduit, a tank, a valve, apump, a filter, a screen, a sensor, or a port.
 70. The system of claim69, further comprising a microreactor arranged downstream of the highpressure pump that has a minimum channel dimension of equal to or lessthan 500 microns.
 71. The system of claim 70, wherein: the feed pump isadapted to pump the first feed stream downstream at an actively,automatically controlled rate; and the high pressure pump is adapted topressurize the first and second feed streams to an elevated pressure ofat least 35 MPa.
 72. The system of claim 70, further comprising acooling unit arranged downstream of the microreactor.
 73. The system ofclaim 69, wherein the component is a check valve, a flow control valve,a mixing valve, or a solenoid valve.
 74. The system of claim 69, whereinthe component is a feed pump, a peristaltic pump, a centrifugal pump, asyringe pump, a metering pump, or a pressurized vessel.
 75. The systemof claim 69, wherein the component is a temperature sensor, a levelsensor, an empty-full pipe sensor, a flowmeter, or a pressure sensor.76. A system for continuously processing at least two liquid feedstreams, comprising: a feed pump adapted to pump a first feed streamdownstream; a mixer positioned to receive the first feed stream from thefeed pump and a second feed stream from a feed line and adapted to mixthe first and second feed streams to achieve a substantially homogeneousmixture; a high pressure pump positioned to receive the substantiallyhomogeneous mixture from the mixer; and a flow control structure or aflow measurement structure, wherein the flow control structure or theflow measurement structure is coupled (i) between the first and secondfeed streams or (ii) between either the first feed stream or the secondfeed stream and a combined feed stream including the first feed streamand the second feed stream.
 77. The system of claim 76, furthercomprising: a microreactor arranged downstream of the high pressure pumpthat has a minimum channel dimension of equal to or less than 500microns; and a cooling unit arranged downstream of the microreactor. 78.The system of claim 76, wherein the flow control structure is selectedfrom one of the following: a check valve, a flow control valve, a mixingvalve, a solenoid valve, a conduit, an overflow tank, a pressurizedtank, a feed pump, a peristaltic pump, a centrifugal pump, a meteringpump, a syringe pump, a screen, a filter, a sampling port, andelectronics including a microprocessor, a computer, or a programmablelogic controller (PLC).
 79. The system of claim 78, wherein the flowmeasurement structure is a pressure sensor, a level sensor, anempty-full pipe sensor, a flowmeter, or a temperature sensor.
 80. Thesystem of claim 76, wherein: the feed pump is adapted to pump the firstfeed stream downstream at an actively, automatically controlled rate;and the high pressure pump is adapted to pressure the first and secondfeed streams to an elevated pressure of at least 35 MPa.
 81. A systemfor continuously processing at least two liquid feed streams,comprising: a first feed pump adapted to pump a first feed streamdownstream; a mixer positioned to receive the first feed stream from thefirst feed pump and a second feed stream from a feed line and adapted tomix the first and second feed streams to achieve a substantiallyhomogeneous mixture; a high pressure homogenizer positioned to receivethe substantially homogeneous mixture from the mixer; a second feed pumpupstream of the high pressure homogenizer and downstream of the mixerthat feeds the high pressure homogenizer; and a flow control structureor a flow measurement structure, wherein the flow control structure orthe flow measurement structure is coupled (i) between the first andsecond feed streams or (ii) between either the first feed stream or thesecond feed stream and a combined feed stream including the first feedstream and the second feed stream.